Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism

Abstract

Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism. Dopamine (DA) depletion modifies the firing pattern of neurons in the substantia nigra pars reticulata (SNr), shifting their mostly tonic firing toward irregularity and bursting, traits of pathological firing underlying rigidity and postural instability in Parkinson's disease (PD) patients and animal models of Parkinsonism (PS). Drug-induced Parkinsonism (DIP) represents 20 -40% of clinical cases of PS, becoming a problem for differential diagnosis, and is still not well studied with physiological tools. It may co-occur with tardive dyskinesia. Here we use in vitro slice preparations including the SNr to observe drug-induced pathological firing by using drugs that most likely produce it, DA-receptor antagonists (SCH23390 plus sulpiride), to compare with firing patterns found in DA-depleted tissue. The hypothesis is that SNr firing would be similar under both conditions, a prerequisite to the proposal of a similar preparation to test other DIP-producing drugs. Firing was analyzed with three complementary metrics, showing similarities between DA depletion and acute DAreceptor blockade. Moreover, blockade of either nonselective cationic channels or Ca v 3 T-type calcium channels hyperpolarized the membrane and abolished bursting and irregular firing, silencing SNr neurons in both conditions. Therefore, currents generating firing in control conditions are in part responsible for pathological firing. Haloperidol, a DIP-producing drug, reproduced DA-receptor antagonist firing modifications. Since acute DA-receptor blockade induces SNr neuron firing similar to that found in the 6-hydroxydopamine model of PS, output basal ganglia neurons may play a role in generating DIP. Therefore, this study opens the way to test other DIP-producing drugs.NEW & NOTEWORTHY Dopamine (DA) depletion enhances substantia nigra pars reticulata (SNr) neuron bursting and irregular firing, hallmarks of Parkinsonism. Several drugs, including antipsychotics, antidepressants, and calcium channel antagonists, among others, produce drug-induced Parkinsonism. Here we show the first comparison between SNr neuron firing after DA depletion vs. firing found after acute blockade of DA receptors. It was found that firing in both conditions is similar, implying that pathological SNr neuron firing is also a physiological correlate of drug-induced Parkinsonism.

Proliferation of Inhibitory Input to the Substantia Nigra in Experimental Parkinsonism

“…Inhibition of these receptors led to a reduction in firing rate and an increase in the irregularity of ISI, which may imply that in dopamine depleted rats, there was no dendritic release of dopamine, no TRPC3 enhancement and thus a reduction in the spontaneous firing rate in comparison to the naïve rats. These findings are also in line with recent work showing a reduction in firing rate, under two conditions; namely, the blockage of D 1 and D 2 receptors and experimental Parkinsonism in juvenile mice (Cáceres-Chávez et al, 2018). We also identified an increase in irregularity, as did Zhou et al (2009).…”

“…We also identified an increase in irregularity, as did Zhou et al (2009). In contrast to in vivo studies that have reported an increase in the bursting activity of SNr neurons (Murer et al, 1997; Lee et al, 2001; Wang et al, 2010b; Cáceres-Chávez et al, 2018), we rarely encountered bursting activity, which may be due to the use of blockers for glutamatergic inputs in our experiments (Ibáñ Ez-Sandoval et al, 2007; Aceves et al, 2011).…”

“…Other studies have reported an increment, a decrement or no change in spontaneous firing (Sanderson et al, 1986; Murer et al, 1997; Rohlfs et al, 1997; Díaz et al, 2003; Breit et al, 2008; Wang et al, 2010b). Recent in vitro work indicated a decrease in firing rate and an increase in irregularity and bursting behavior of these neurons (Cáceres-Chávez et al, 2018).…”

Cellular and Synaptic Dysfunctions in Parkinson’s Disease: Stepping Out of the Striatum

“…Interestingly, this effect was mimicked by artificially elevating ambient DA levels, which supports its physiological and functional relevance [178]. In addition, acute blockade of D1-like and D2-like receptors induces hyperpolarization of SNr neurons and a switch from tonic regular firing to irregular or burst firing [47]. This pharmacological manipulation resembles the activity of SNr neurons recorded in vivo in anesthetized [179,180,181,182] and awake [183] DD rodents.…”

“…DA release has also been measured in the STN upon electrical stimulation of dopaminergic inputs using fast-scan voltammetry [43]. In addition, DA receptors are expressed in all ESN (for a review, see [46]), and local applications of dopaminergic receptor agonists and antagonists locally in various ESN affect the neuronal activity of these nuclei [47,48,49,50]. All these data suggest that DA participates in the normal function of the ESN by regulating both cellular excitability and synaptic transmission.…”